NM_003560.4(PLA2G6):c.757G>A (p.Gly253Ser) AND Infantile neuroaxonal dystrophy

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Oct 17, 2022
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000995607.6

Allele description [Variation Report for NM_003560.4(PLA2G6):c.757G>A (p.Gly253Ser)]

NM_003560.4(PLA2G6):c.757G>A (p.Gly253Ser)

Gene:

PLA2G6:phospholipase A2 group VI [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

22q13.1

Genomic location:

Preferred name:

NM_003560.4(PLA2G6):c.757G>A (p.Gly253Ser)

Other names:

NM_003560.4(PLA2G6):c.757G>A; p.Gly253Ser

HGVS:

NC_000022.11:g.38140022C>T
NG_007094.3:g.79757G>A
NM_001004426.3:c.757G>A
NM_001199562.3:c.757G>A
NM_001349864.2:c.757G>A
NM_001349865.2:c.757G>A
NM_001349866.2:c.757G>A
NM_001349867.2:c.223G>A
NM_001349868.2:c.119+3083G>A
NM_001349869.2:c.223G>A
NM_003560.4:c.757G>AMANE SELECT
NP_001004426.1:p.Gly253Ser
NP_001186491.1:p.Gly253Ser
NP_001336793.1:p.Gly253Ser
NP_001336794.1:p.Gly253Ser
NP_001336795.1:p.Gly253Ser
NP_001336796.1:p.Gly75Ser
NP_001336798.1:p.Gly75Ser
NP_003551.2:p.Gly253Ser
LRG_1015t1:c.757G>A
LRG_1015:g.79757G>A
LRG_1015p1:p.Gly253Ser
NC_000022.10:g.38536029C>T
NC_000022.10:g.38536029C>T
NG_007094.2:g.70669G>A

Protein change:

G253S

Links:

dbSNP: rs745643715

NCBI 1000 Genomes Browser:

rs745643715

Molecular consequence:

NM_001349868.2:c.119+3083G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001004426.3:c.757G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001199562.3:c.757G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001349864.2:c.757G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001349865.2:c.757G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001349866.2:c.757G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001349867.2:c.223G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001349869.2:c.223G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003560.4:c.757G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Infantile neuroaxonal dystrophy (NBIA2A)
Synonyms:: NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 2A; Seitelberger disease; Infantile neuroaxonal dystrophy 1
Identifiers:: MONDO: MONDO:0024457; MedGen: C0270724; Orphanet: 35069; OMIM: 256600

Recent activity

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NF-kappa-B inhibitor zeta isoform a [Homo sapiens]
NF-kappa-B inhibitor zeta isoform a [Homo sapiens]
gi|13899229|ref|NP_113607.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001149883	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Likely pathogenic (May 7, 2019)	germline	clinical testing	Citation Link,
SCV003454502	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 17, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33098801, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001149883

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

criteria provided, single submitter

(Classification criteria August 2017)

Likely pathogenic
(May 7, 2019)

germline

clinical testing

Citation Link,

SCV003454502

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 17, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Monogenic variants in dystonia: an exome-wide sequencing study.

Zech M, Jech R, Boesch S, Škorvánek M, Weber S, Wagner M, Zhao C, Jochim A, Necpál J, Dincer Y, Vill K, Distelmaier F, Stoklosa M, Krenn M, Grunwald S, Bock-Bierbaum T, Fečíková A, Havránková P, Roth J, Příhodová I, Adamovičová M, Ulmanová O, et al.

Lancet Neurol. 2020 Nov;19(11):908-918. doi: 10.1016/S1474-4422(20)30312-4.

PubMed [citation]

PMID:: 33098801
PMCID:: PMC8246240

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV001149883.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	blood	not provided		1	not provided	not provided	not provided

From Invitae, SCV003454502.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 253 of the PLA2G6 protein (p.Gly253Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of PLA2G6-related conditions (PMID: 33098801). ClinVar contains an entry for this variant (Variation ID: 807465). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PLA2G6 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 26, 2024

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